Polymorphic form of alcaftadine, composition and process

ABSTRACT

The present invention relates to novel polymorphic forms of alcaftadine, processes of preparing novel polymorphic forms of alcaftadine and pharmaceutical compositions thereof.

FIELD OF THE INVENTION

The present invention relates to novel polymorphic forms of alcaftadine.The present invention further relates to processes of preparing novelpolymorphic forms of alcaftadine and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION

Alcaftadine is chemically 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2, 1-b] [3]benzazepine-3-carboxaldehyde and is known from U.S. Pat. No. 5,468,743and is represented by a compound of structural formula

Alcaftadine is a H1 histamine receptor antagonist sold in USA under theproprietary name of “LASTACAFT” and is indicated for the prevention ofitching associated with allergic conjunctivitis.

The process of preparing alcaftadine compound of structural formula I isdisclosed in U.S. Pat. No. 5,468,743 for preparing “alcaftadineanalogous compound”, which is represented below in Scheme I, Scheme IIand Scheme III. The alcaftadine obtained according to Scheme I, SchemeII and Scheme III, is characterized by having a melting point of 171.6°C. (referred herein after as Form I).

Scheme I is shown as follows:

Scheme II is shown as follows:

Scheme III is shown as follows:

A survey of the literature on alcaftadine did not provide any referenceto its crystal structure or the possibility of different polymorphs.Information about the solid-state properties of a drug substance isimportant. For example, different forms may have significantly differentsolubilities. Further, the handling and stability of a drug substancemay depend critically on the solid state of the drug.

Polymorphism is defined as “the ability of a compound to crystallize inmore than one distinct crystal species” and different crystalarrangements of the same chemical compound are termed as polymorphs.Polymorphs of the same compound arise due to difference in the internalarrangement of atoms. Different polymorphs have different free energiesand therefore have different physical properties such as solubility,chemical stability, melting point, density, flow properties,bioavailability and so forth.

The inventors of the present application have found that alcaftadine canexhibit polymorphism (i.e., alcaftadine can exist in differentpolymorphic forms) and accordingly, novel polymorphic forms ofalcaftadine are provided.

SUMMARY OF THE INVENTION

A first aspect of the present invention is to provide novel polymorphicforms of alcaftadine.

According to another aspect, the present invention relates tocrystalline forms of alcaftadine.

According to another aspect, the present invention relates to anα-crystalline form of alcaftadine.

According to another aspect, the present invention relates to a processfor the preparation of α-crystalline form of alcaftadine.

According to another aspect, the present invention relates to a processof preparing α-crystalline form of alcaftadine comprising the steps of:

-   -   a) suspending crude alcaftadine in an organic solvent to obtain        a suspension;    -   b) stirring the suspension obtained in the step of suspending        crude alcaftadine; and    -   c) isolating an α-crystalline form of alcaftadine.

According to another aspect, the present invention relates to a processof preparing α-crystalline form of alcaftadine comprising the steps of:

-   -   a) suspending crude alcaftadine in a ketone solvent to obtain a        suspension;    -   b) stirring the suspension obtained in the step of suspending        crude alcaftadine; and    -   c) Isolating an α-crystalline form of alcaftadine.

According to another aspect, the present invention relates to aβ-crystalline form of alcaftadine.

According to another aspect, the present invention relates to processfor the preparation of β-crystalline form of alcaftadine.

According to another aspect, the present invention relates to a processof preparing β-crystalline form of alcaftadine comprising the steps of:

-   -   a) suspending crude alcaftadine in an organic solvent to obtain        a suspension;    -   b) stirring the suspension obtained in the step of suspending        crude alcaftadine; and    -   c) isolating a β-crystalline form of alcaftadine.

Another aspect of the present invention is to provide an amorphous formof alcaftadine.

Another aspect of the present invention is to provide process for thepreparation of an amorphous form of alcaftadine.

Another aspect of the present invention is to provide a process ofpreparing an amorphous form of alcaftadine comprising the steps of:

-   -   a) preparing a solution of alcaftadine in an organic solvent;        and    -   b) recovering alcaftadine in the amorphous form from said        solution by removing solvent by using techniques selected from        the group consisting of spray-drying and freeze-drying.

Another aspect of the present invention is to provide a process ofpreparing an amorphous form of alcaftadine comprising the steps of:

-   -   a) preparing a solution of alcaftadine in an organic solvent;    -   b) removing a solvent from the solution obtained by preparing a        solution of alcaftadine, by using agitated thin film drying; and    -   c) recovering alcaftadine in the amorphous form from the        agitated thin film dryer.

Another aspect of the present invention is to provide a process ofpreparing an amorphous form of alcaftadine comprising the steps of:

-   -   a) melting a crystalline form of alcaftadine; and    -   b) Recovering alcaftadine in an amorphous form.

Another aspect of the present invention is to provide a pharmaceuticalcomposition comprising an α-crystalline form of alcaftadine.

Another aspect of the present invention is to provide a pharmaceuticalcomposition comprising a β-crystalline form of alcaftadine.

Another aspect of the present invention is to provide a pharmaceuticalcomposition comprising an amorphous form of alcaftadine.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the invention will become apparentfrom reading the following detailed description in conjunction with thefollowing drawings, in which like reference numbers refer to like parts.

FIG. 1 depicts an X-ray diffraction pattern of α-crystalline form ofalcaftadine.

FIG. 2 depicts an infrared spectra of α-crystalline form of alcaftadine.

FIG. 3 depicts an X-ray diffraction pattern of β-crystalline form ofalcaftadine.

FIG. 4 depicts an infrared spectra of β-crystalline form of alcaftadine.

DETAILED DESCRIPTION

The examples and the referenced drawings in this detailed descriptionare merely exemplary, and should not be used to limit the scope of theclaims in any claim construction or interpretation.

The present invention relates to novel polymorphic forms of alcaftadineand a process for the preparation thereof.

The present invention further relates to an α-crystalline form ofalcaftadine characterized by X-ray diffraction pattern having peaks at8.3, 10.9, 12.7, 14.7, 15.1, 15.4, 16.0, 16.5, 17.2, 17.7, 18.7, 19.1,19.9, 21.1, 22.0, 22.7, 24.1, 24.7, 25.1, 26.3, 26.7, 27.2, 28.0,28.5±0.2 degrees 2θ.

In another embodiment, the present invention relates to an α-crystallineform of alcaftadine characterized by an X-ray diffraction pattern asdepicted in FIG. 1.

In another embodiment, the present invention relates to an α-crystallineform of alcaftadine characterized by an infrared spectrum as depicted inFIG. 2.

In another embodiment, the present invention relates to a β-crystallineform of alcaftadine characterized by an X-ray diffraction pattern havingpeaks at 10.0, 11.4, 12.0, 15.5, 16.2, 18.4, 19.6, 20.2, 20.5, 22.0,23.1, 23.5, 24.6, 25.4, 25.8, 28.8, 31.3±0.2 degrees 2θ.

In another embodiment, the present invention relates to a β-crystallineform of alcaftadine characterized by an X-ray diffraction pattern asdepicted in FIG. 3.

In another embodiment, the present invention relates to a β-crystallineform of alcaftadine characterized by an infrared spectrum as depicted inFIG. 4.

The crude alcaftadine as used according to the present invention can beprepared by methods disclosed in the art such as those described in U.S.Pat. No. 5,468,743, which is incorporated herein by reference.

In another embodiment, the α-crystalline form of alcaftadine is preparedby suspending crude alcaftadine in an organic solvent, stirring theresulting suspension at a temperature in the range of 0° C. to 50° C.for a period in the range of 30 minutes to 6 hours and isolating theα-crystalline form of alcaftadine from the suspension.

In yet another embodiment, the β-crystalline form of alcaftadine isprepared by suspending crude alcaftadine in an organic solvent, stirringthe resulting suspension at a temperature in the range of 0° C. to 50°C. for a period in the range of 30 minutes to 8 hours and isolating theβ-crystalline form of alcaftadine from the suspension.

An organic solvent according to the present invention can be selectedfrom the group comprising, but not limited to, alcohols, furans, ethers,ketones, nitriles, esters, hydrocarbons such as halogenated aliphatichydrocarbon solvents or the like or mixtures thereof. Ketone solvent canbe selected from the group comprising, but not limited to acetone,methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethylketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methylpropyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone ormixture(s) thereof.

The ether solvent can be selected from the group comprising, but notlimited to, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether,dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methylisobutyl ether or mixture(s) thereof.

The alcohol solvents can be selected from the group comprising, but notlimited to, methanol, ethanol, propanol, isopropanol, butanol,isobutanol, t-butanol, pentanol or mixture(s) thereof.

The ester solvents can be selected from the group comprising, but notlimited to, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof.

The nitrile solvents can be selected from the group comprising, but notlimited to, acetonitrile, propionitrile or mixture(s) thereof.

The halogenated aliphatic hydrocarbon solvents can be selected from thegroup comprising, but not limited to, dichloromethane, dichloroethane,chloroform, carbon tetrachloride or mixture(s) thereof.

The crystalline forms (α and/or β) of alcaftadine may be isolated by anyknown process in the art such as filtration, centrifugation, washing,drying or the combinations thereof.

The isolated crystalline forms (α and/or β) of alcaftadine may be driedat a temperature in the range of 40° C. to 110° C. for a period of 2hours to 12 hours under reduced pressure.

A solution of crude alcaftadine in an organic solvent may be prepared bydissolving alcaftadine in an organic solvent at a temperature in therange of 20° C. to 60° C.

Alternatively, such a solution may be obtained directly from a reactionin which alcaftadine is formed.

In another embodiment according to present invention, the solvent may beremoved from the solution by a technique which includes, for example,spray drying and freeze drying.

In one aspect, an amorphous form of alcaftadine may be recovered fromthe solution using a spray drying technique. A Mini-Spray Dryer (Model:Buchi 190, Switzerland) can be used. The Buchi 190 Mini-Spray Dryeroperates on the principle of nozzle spraying in a parallel flow, i.e.,the sprayed product and the drying gas flow in the same direction. Thedrying gas can be air or inert gases such as nitrogen, argon and carbondioxide.

In another aspect, an amorphous form of alcaftadine may be recoveredfrom the solution using a freeze drying technique. A freeze dryer(Model; Virtis Genesis SQ Freeze Dryer) can be used in this technique.The Virtis Genesis SQ Freeze Dryer operates on the principle oflyophilization, i.e., a process of stabilizing initially wet materials(aqueous solution or suspensions) by freezing them, then subliming theice while simultaneously desorbing some of the bound moisture (primarydrying). Following removal of the ice, desorption may be continued(secondary drying). This process may be carried out under vacuum.

The spray drying may be accomplished using a spray dryer which operateson the principle of nozzle spraying in a parallel flow (i.e., thesprayed product and the drying gas flowing in the same direction). Thedrying gas can be air or one or more inert gases such as nitrogen,argon, and carbon dioxide. Moreover, the product obtained may be furtheror additionally dried to achieve the desired moisture values. Forexample, the product may be further or additionally dried in a traydrier, dried under vacuum and/or in a Fluid Bed Dryer.

The solution of alcaftadine may be optionally treated with activatedcharcoal and the resulting solution is filtered through hyflo bed to getfiltrate.

The resulting filtrate is fed into an agitated thin film dryer (ATFD).The solvent is subsequently removed from the solution by agitated thinfilm drying.

The drying process may be accompanied by heating at a temperature in therange of 30° C. to 60° C. under reduced pressure.

The feeding rate of the solution may be controlled in such a way tofacilitate the thin film formation and the evaporation rate. The rotorand vapor duct can have a sealing system so that the drying canpreferably be carried under vacuum. Vacuum operation also facilitatesamorphous form of alcaftadine to be obtained without degradation.

The crystalline form of alcaftadine may be melted at a temperature inthe range of 160° C. to 190° C.

The amorphous form of alcaftadine may be recovered by the steps ofcooling and milling of melted alcaftadine. The milling of meltedalcaftadine may be carried out in a mortar and pestle.

The cooling of melted alcaftadine may be carried out up to thetemperature in the range of 20-30° C.

The term “recovering alcaftadine in the amorphous form,” according tothe claimed invention, includes unloading, amassing, gathering, scalingand/or piling amorphous form of alcaftadine.

The amorphous form of alcaftadine may be optionally further dried undervacuum at a temperature in the range of 40° C. to 110° C. for 2 hours to8 hours to obtain an amorphous form of alcaftadine with desired residualsolvent content.

In another embodiment, the present invention relates to thepharmaceutical composition of alcaftadine comprising an α-crystallineform of alcaftadine and one or more pharmaceutically acceptableexcipients.

In another embodiment, the present invention relates to thepharmaceutical composition of alcaftadine comprising a β-crystallineform of alcaftadine and one or more pharmaceutically acceptableexcipients.

In another embodiment, the present invention relates to thepharmaceutical composition of alcaftadine comprising an amorphous formof alcaftadine and one or more pharmaceutically acceptable excipients.

The pharmaceutical composition of alcaftadine may be in the form of anophthalmic solution.

An ophthalmic solution of alcaftadine may have an alcaftadine activeingredient in the range of 0.05 to 0.25% weight/weight.

The pharmaceutical excipients may be selected from the group consistingof sodium phosphate, edetate disodium, benzalkonium chloride and sodiumchloride.

The pH of an ophthalmic solution of alcaftadine may be adjusted by anaqueous solution of sodium hydroxide or hydrochloric acid.

An X-ray diffraction (XRD) measurement was performed on X-Ray powderdiffractometer Bruker D8 Advance powder diffractometer with the detectorLynxeye (Bruker). The analysis conditions were as follows:

Scan range [°2-theta]: 2-39.98;

Scan mode: Continuous;

Step size [°2-theta]: 0.0170;

Scan step time[s]: 51.04 seconds;

Sample spin: 15 rpm;

Sample holder: glass;

Measurement Temperature [° C.]: 25

Anode Material: Cu

K-Alpha [Å]: 1.54060

Prior to analysis, the samples were gently ground by means of mortar andpestle in order to obtain a fine powder. The sample might be mixed withn-dodecane in order to avoid the environment contamination by airborneparticles coming from the powder. The ground sample or its suspensionwith n-dodecane was adjusted into a cavity of the sample holder and thesurface of the sample was smoothed by means of a cover glass.

EXAMPLES

In the following examples, the preferred embodiments of the presentinvention are described only by way of illustrating the process of theinvention. However, these are not intended to limit the scope of thepresent invention in any way.

Example 1 Preparation of an α-Crystalline Form of Alcaftadine

Crude alcaftadine (10 grams) was suspended in acetone (30 ml) at 25° C.and resulting suspension was stirred for 3 hours at 25° C. The resultingsolid was filtered, washed with acetone (10 ml) and then dried at 45° C.for 8 hours under reduced pressure.

Yield: 9.7 grams and Purity: 99.96% (By HPLC)

XRD: As depicted in FIG. 1.

IR: As depicted in FIG. 2.

Example 2 Preparation of β-Crystalline Form of Alcaftadine

Crude alcaftadine (10 grams) was suspended in diethyl ether (40 ml) at25-30° C. and resulting suspension was stirred for 2 hours at 25° C. Theresulting solid was filtered, washed with diethyl ether (10 ml) and thendried at 50° C. for 12 hours under reduced pressure.

Yield: 9.8 grams and Purity: 99.87% (By HPLC)

XRD: As depicted in FIG. 3.

IR: As depicted in FIG. 4.

Example 3 Preparation of an Amorphous Form of Alcaftadine

Crystalline alcaftadine (10 grams) was dissolved in isopropanol (60 ml)at 30-40° C. The clear solution was subjected to spray drying in a minispray dryer at an inlet temperature of 80° C. and an outlet temperatureof 50° C. with a feed rate of 15 ml/minute. Alcaftadine in an amorphousform was thus isolated.

Yield: 9.5 grams and purity: 99.97% (By HPLC)

Example 4 Preparation of an Amorphous Form of Alcaftadine

A solution of alcaftadine (100 grams) in methanol (1200 ml) was fed intoan agitated thin film dryer at a vacuum in the range of 50-100 mm Hg anda jacket temperature in the range of 45-54° C. The obtained solid wasdried under reduced pressure at a temperature of 70° C. for 5 hours toobtain amorphous alcaftadine.

Yield: 82 grams and Purity: 99.85% (By HPLC)

Example 5 Preparation of an Amorphous Form of Alcaftadine

A solution of alcaftadine (100 grams) in methanol (1200 ml) was treatedwith activated charcoal (10 grams) and the resulting solution wasfiltered through hyflo bed to get filtrate. The resulting filtrate wasfed into an agitated thin film dryer at a vacuum in the range of 50-100mm Hg and a jacket temperature in the range of 45-54° C. The obtainedsolid was dried in a vacuum tray dryer under reduced pressure at 70° C.for 6 hours to obtain amorphous alcaftadine.

Yield: 80 grams and Purity: 99.95% (By HPLC)

Example 6 Preparation of an Amorphous Form of Alcaftadine

A crystalline form of alcaftadine (10 grams) was placed in an oven at175° C. for 45 minutes. The melted alcaftadine was cooled to 25° CC andthen the obtained solid was milled in a mortar and pestle to obtainamorphous alcaftadine.

Yield: 9.8 grams and Purity: 99.94% (By HPLC)

The scope of the claims should not be limited by the preferredembodiments and examples, but should be given the broadestinterpretation consistent with the specification as a whole.

What is claimed is:
 1. An α-crystalline form of alcaftadine havingcharacteristics of X-ray diffraction peaks at 8.3, 10.9, 12.7, 14.7,15.1, 15.4, 16.0, 16.5, 17.2, 17.7, 18.7, 19.1, 19.9, 21.1, 22.0, 22.7,24.1, 24.7, 25.1, 26.3, 26.7, 27.2, 28.0, 28.5±0.2 degrees 2θ.
 2. Aprocess of preparing an α-crystalline form of alcaftadine comprising thesteps of: a) suspending crude alcaftadine in an organic solvent toobtain a suspension; b) stirring the suspension obtained in the step ofsuspending crude alcaftadine; and c) isolating an α-crystalline form ofalcaftadine.
 3. The process according to claim 2, wherein the suspensionis stirred at a temperature in the range of 0° to 50° C. for a period of30 minutes to 6 hours.
 4. The process according to claim 2, wherein theorganic solvent is a ketone solvent selected from the group consistingof acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone,diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butylketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropylketone and mixture(s) thereof.
 5. The process according to claim 2,wherein the α-crystalline form of alcaftadine is isolated by the stepsof filtration, centrifugation, washing, drying and combinations thereof.6. The process according to claim 5, wherein the isolated α-crystallineform of alcaftadine is dried at a temperature in the range of 40° C. to110° C. for a period of 2 hours to 12 hours under reduced pressure.